The ability of T lymphocytes to recognize diverse ligands (antigens) resides in the T cell receptor (TCR), which is a heterodimer constructed from somatically rearranging variable (V) diversity (D) and joining (J) elements to account for its diversity, while each gene contains an invariant constant region. Most mature, effector T lymphocytes express the same class of TCR constant region, termed alpha/beta, but a smaller subclass of T cells appearing early in thymic ontogeny has been found to express a different heterodimer, termed gamma/delta. The function, the ligand, and the genetic regulation of this second receptor has been previously unknown although genetic clones for the gamma TCR existed. This project seeks to define and clone the delta TCR gene encoding the remaining chain or the second heterodimer, and to understand how genetic selection of the alpha/beta vs. gamma/delta TCR is accomplished. During the last year, our laboratory and two other laboratories independently cloned the delta TCR gene utilizing the discovery that the delta TCR gene is tightly linked to the alpha TCR gene. These studies have established that the genetic order on human chromosome 14 is V-D-J delta-C delta-J alpha-C alpha, meaning that components of the alpha TCR flank the delta TCR on both sides. We have discovered an important regulatory rearrangement which deletes the delta TCR and which appears to be the initial step in alpha TCR gene usage. Consequently, a cell selects either gamma/delta or alpha/beta gene usage, so that these T cells derive from two different cell lineages. The regulatory rearrangement shares many common features with two immunoglobulin regulatory recombination events (class switching and kappa gene deletion). The study of the proteins involved in alpha versus delta TCR selection may lead to a better understanding of the regulation of gene rearrangement and may clarify the mechanisms of T cell maturation and selection within the thymus.